How Long Until It Works

• 1–3 weeks

If It Works

• The goal of treatment is complete remission of symptoms (i.e., mania and/or depression)

• Continue treatment until all symptoms are gone or until improvement is stable and then continue treating indefinitely as long as improvement persists

• Continue treatment indefinitely to avoid recurrence of mania or depression

If It Doesn’t Work

✽ Many patients have only a partial response where some symptoms are improved but others persist or continue to wax and wane without stabilization of mood

• Other patients may be nonresponders, sometimes called treatment-resistant or treatment-refractory

• Consider checking plasma drug level, increasing dose, switching to another agent or adding an appropriate augmenting agent

• Consider adding psychotherapy

• Consider the presence of noncompliance and counsel patient

• Switch to another mood stabilizer with fewer side effects

• Consider evaluation for another diagnosis or for a comorbid condition (e.g., medical illness, substance abuse, etc.)

Best Augmenting Combos for Partial Response or Treatment Resistance

• Valproate

• Atypical antipsychotics (especially risperidone, olanzapine, quetiapine, ziprasidone, and aripiprazole)

• Lamotrigine

✽ Antidepressants (with caution because antidepressants can destabilize mood in some patients, including induction of rapid cycling or suicidal ideation; in particular consider bupropion; also SSRIs, SNRIs, others; generally avoid TCAs, MAOIs)

Tests

✽ Before initiating treatment, kidney function tests (including creatinine and urine specific gravity) and thyroid function tests; electrocardiogram for patients over 50

• Repeat kidney function tests 1–2 times/year

✽ Frequent tests to monitor trough lithium plasma levels (should generally be between 1.0 and 1.5 mEq/L for acute treatment, 0.6 and 1.2 mEq/l for chronic treatment)

✽ Since lithium is frequently associated with weight gain, before starting treatment, weigh all patients and determine if the patient is already overweight (BMI 25.0–29.9) or obese (BMI ≥30)

• Before giving a drug that can cause weight gain to an overweight or obese patient, consider determining whether the patient already has pre-diabetes (fasting plasma glucose 100–125 mg/dL), diabetes (fasting plasma glucose >126 mg/dL), or dyslipidemia (increased total cholesterol, LDL cholesterol, and triglycerides; decreased HDL cholesterol), and treat or refer such patients for treatment, including nutrition and weight management, physical activity counseling, smoking cessation, and medical management

✽ Monitor weight and BMI during treatment

✽ While giving a drug to a patient who has gained >5% of initial weight, consider evaluating for the presence of pre-diabetes, diabetes, or dyslipidemia, or consider switching to a different agent

LITHIUM: SIDE EFFECTS

How Drug Causes Side Effects

• Unknown and complex

• CNS side effects theoretically due to excessive actions at the same or similar sites that mediate its therapeutic actions

• Some renal side effects theoretically due to lithium’s actions on ion transport

Notable Side Effects

✽ Ataxia, dysarthria, delirium, tremor, memory problems

✽ Polyuria, polydipsia (nephrogenic diabetes insipidus)

✽ Diarrhea, nausea

✽ Weight gain

• Euthyroid goiter or hypothyroid goiter, possibly with increased TSH and reduced thyroxine levels

• Acne, rash, alopecia

• Leukocytosis

• Side effects are typically dose-related

Life-Threatening or Dangerous Side Effects

• Lithium toxicity

• Renal impairment (interstitial nephritis)

• Nephrogenic diabetes insipidus

• Arrhythmia, cardiovascular changes, sick sinus syndrome, bradycardia, hypotension

• T wave flattening and inversion

• Rare pseudotumor cerebri

• Rare seizures

Weight Gain

• Many experience and/or can be significant in amount

• Can become a health problem in some

• May be associated with increased appetite

Sedation

• Many experience and/or can be significant in amount

• May wear off with time

What to Do About Side Effects

• Wait

• Wait

• Wait

• Lower the dose

✽ Take entire dose at night as long as efficacy persists all day long with this administration

✽ Change to a different lithium preparation (e.g., controlled-release)

✽ Reduce dosing from 3 times/day to 2 times/day

• If signs of lithium toxicity occur, discontinue immediately

• For stomach upset, take with food

• For tremor, avoid caffeine

• Switch to another agent

Best Augmenting Agents for Side Effects

✽ Propranolol 20–30 mg 2–3 times/day may reduce tremor

• For the expert, cautious addition of a diuretic (e.g., chlorothiazide 50 mg/day) while reducing lithium dose by 50% and monitoring plasma lithium levels may reduce polydipsia and polyuria that does not go away with time alone

• Many side effects cannot be improved with an augmenting agent

LITHIUM: DOSING AND USE

Usual Dosage Range

• 1,800 mg/day in divided doses (acute)

• 900–1,200 mg/day in divided doses (maintenance)

• Liquid: 10 mL three times/day (acute mania); 5 mL 3–4 times/day (long-term)

Dosage Forms

• Tablet 300 mg (slow-release), 450 mg (controlled-release)

• Capsule 150 mg, 300 mg, 600 mg

• Liquid 8 mEq/5 mL

How to Dose

• Start 300 mg 2–3 times/day and adjust dosage upward as indicated by plasma lithium levels

Dosing Tips

✽ Sustained-release formulation may reduce gastric irritation, lower peak lithium plasma levels, and diminish peak dose side effects (i.e., side effects occurring 1–2 hours after each dose of standard lithium carbonate may be improved by sustained-release formulation)

• Lithium sulfate and other dosage strengths for lithium are available in Europe

• Check therapeutic blood levels as “trough” levels about 12 hours after the last dose

• After stabilization, some patients may do best with a once daily dose at night

• Responses in acute mania may take 7–14 days even with adequate plasma lithium levels

✽ Some patients apparently respond to doses as low as 300 mg twice a day, even with plasma lithium levels below 0.5 mEq/L

• Use the lowest dose of lithium associated with adequate therapeutic response

• Lower doses and lower plasma lithium levels (<0.6 mEq/L) are often adequate and advisable in the elderly

✽ Rapid discontinuation increases the risk of relapse and possibly suicide, so lithium may need to be tapered slowly over 3 months if it is to be discontinued after long-term maintenance

Overdose

• Fatalities have occurred; tremor, dysarthria, delirium, coma, seizures, autonomic instability

Long-Term Use

• Indicated for long-term prevention of relapse

• May cause reduced kidney function

• Requires regular therapeutic monitoring of lithium levels as well as of kidney function and thyroid function

Habit Forming

• No

How to Stop

• Taper gradually over 3 months to avoid relapse

• Rapid discontinuation increases the risk of relapse, and possibly suicide

• Discontinuation symptoms uncommon

Pharmacokinetics

• Half life 18–30 hours

Drug Interactions

✽ Non-steroidal anti-inflammatory agents, including ibuprofen and selective COX-2 inhibitors (cyclooxygenase 2), can increase plasma lithium concentrations; add with caution to patients stabilized on lithium

✽ Diuretics, especially thiazides, can increase plasma lithium concentrations; add with caution to patients stabilized on lithium

• Angiotensin-converting enzyme inhibitors can increase plasma lithium concentrations; add with caution to patients stabilized on lithium

• Metronidazole can lead to lithium toxicity through decreased renal clearance

• Acetazolamide, alkalizing agents, xanthine preparations, and urea may lower lithium plasma concentrations

• Methyldopa, carbamazepine, and phenytoin may interact with lithium to increase its toxicity

• Use lithium cautiously with calcium channel blockers, which may also increase lithium toxicity

• Use of lithium with an SSRI may raise risk of dizziness, confusion, diarrhea, agitation, tremor

• Some patients taking haloperidol and lithium have developed an encephalopathic syndrome similar to neuroleptic malignant syndrome

• Lithium may prolong effects of neuromuscular blocking agents

• No likely pharmacokinetic interactions of lithium with mood-stabilizing anticonvulsants or atypical antipsychotics